Background:Aducanumab(Adu),which is a human IgG1 monoclonal antibody that targets oligomer and fibril forms of beta-amyloid,has been reported to reduce amyloid pathology and improve impaired cognition after administra...Background:Aducanumab(Adu),which is a human IgG1 monoclonal antibody that targets oligomer and fibril forms of beta-amyloid,has been reported to reduce amyloid pathology and improve impaired cognition after administration of a high dose(10 mg/kg)of the drug in Alzheimer’s disease(AD)clinical trials.The purpose of this study was to investigate the effects of a lower dose of Adu(3 mg/kg)with enhanced delivery via focused ultrasound(FUS)in an AD mouse model.Methods:The FUS with microbubbles opened the blood-brain barrier(BBB)of the hippocampus for the delivery of Adu.The combined therapy of FUS and Adu was performed three times in total and each treatment was performed biweekly.Y-maze test,Brdu labeling,and immunohistochemical experimental methods were employed in this study.In addition,RNA sequencing and ingenuity pathway analysis were employed to investigate gene expression profiles in the hippocampi of experimental animals.Results:The FUS-mediated BBB opening markedly increased the delivery of Adu into the brain by approximately 8.1 times in the brains.The combined treatment induced significantly less cognitive decline and decreased the level of amyloid plaques in the hippocampi of the 5×FAD mice compared with Adu or FUS alone.Combined treatment with FUS and Adu activated phagocytic microglia and increased the number of astrocytes associated with amyloid plaques in the hippocampi of 5×FAD mice.Furthermore,RNA sequencing identified that 4 enriched canonical pathways including phagosome formation,neuroinflammation signaling,CREB signaling and reelin signaling were altered in the hippocami of 5×FAD mice receiving the combined treatment.Conclusion:In conclusion,the enhanced delivery of a low dose of Adu(3 mg/kg)via FUS decreases amyloid deposits and attenuates cognitive function deficits.FUS-mediated BBB opening increases adult hippocampal neurogenesis as well as drug delivery.We present an AD treatment strategy through the synergistic effect of the combined therapy of FUS and Adu.展开更多
Alzheimer’s disease(AD)is the most common type of dementia.Monoclonal antibodies(MABs)serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors,such as amyloid-β(Aβ)peptide,ta...Alzheimer’s disease(AD)is the most common type of dementia.Monoclonal antibodies(MABs)serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors,such as amyloid-β(Aβ)peptide,tau protein,and neuroinflammation.Specifically,based on their efficacy in removing Aβplaques from the brains of patients with AD,the U.S.Food and Drug Administration has approved three anti-amyloid MABs,aducanumab(AduhelmR),lecanemab(LeqembiR),and donanemab(Kisunla™).Notably,lecanemab received traditional approval after demonstrating clinical benefit,supporting the Aβcascade hypothesis.These MABs targeting Aβare categorized based on their affinity to diverse conformational features of Aβ,including monomer,fibril,protofibril,and plaque forms of Aβas well as pyroglutamate Aβ.First-generation MABs targeting the non-toxic monomeric Aβ,such as solanezumab,bapineuzumab,and crenezumab,failed to demonstrate clinical benefit for AD in clinical trials.In contrast,secondgeneration MABs,including aducanumab,lecanemab,donanemab,and gantenerumab directed against pathogenic Aβspecies and aggregates have shown that reducing Aβdeposition can be an effective strategy to slow cognitive impairment in AD.In this review,we provide a comprehensive overview of the current status,mechanisms,outcomes,and limitations of second-generation MABs for the clinical treatment of AD.Moreover,we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.展开更多
基金the Healthcare Technology R&D Project(HI19C0060)by the Ministry for Health,Welfare,and Family Affairs,Republic of KoreaIn addition,this work was supported by Seoul National University Bundang Hospital Research Fund,South Korea(14-2021-0004)National Research Foundation of Korea(NRF)grant funded by the Korea government(MIST)(Grant no.2020R1A2C1011839)to HS.Kim.Also,H.Kim and EJ.Yang received a scholarship from the BK21-Plus Education Program provided by the National Research Foundation of Korea.
文摘Background:Aducanumab(Adu),which is a human IgG1 monoclonal antibody that targets oligomer and fibril forms of beta-amyloid,has been reported to reduce amyloid pathology and improve impaired cognition after administration of a high dose(10 mg/kg)of the drug in Alzheimer’s disease(AD)clinical trials.The purpose of this study was to investigate the effects of a lower dose of Adu(3 mg/kg)with enhanced delivery via focused ultrasound(FUS)in an AD mouse model.Methods:The FUS with microbubbles opened the blood-brain barrier(BBB)of the hippocampus for the delivery of Adu.The combined therapy of FUS and Adu was performed three times in total and each treatment was performed biweekly.Y-maze test,Brdu labeling,and immunohistochemical experimental methods were employed in this study.In addition,RNA sequencing and ingenuity pathway analysis were employed to investigate gene expression profiles in the hippocampi of experimental animals.Results:The FUS-mediated BBB opening markedly increased the delivery of Adu into the brain by approximately 8.1 times in the brains.The combined treatment induced significantly less cognitive decline and decreased the level of amyloid plaques in the hippocampi of the 5×FAD mice compared with Adu or FUS alone.Combined treatment with FUS and Adu activated phagocytic microglia and increased the number of astrocytes associated with amyloid plaques in the hippocampi of 5×FAD mice.Furthermore,RNA sequencing identified that 4 enriched canonical pathways including phagosome formation,neuroinflammation signaling,CREB signaling and reelin signaling were altered in the hippocami of 5×FAD mice receiving the combined treatment.Conclusion:In conclusion,the enhanced delivery of a low dose of Adu(3 mg/kg)via FUS decreases amyloid deposits and attenuates cognitive function deficits.FUS-mediated BBB opening increases adult hippocampal neurogenesis as well as drug delivery.We present an AD treatment strategy through the synergistic effect of the combined therapy of FUS and Adu.
基金funded by Basic Science Research Program of the National Research Foundation of Korea(NRF)which is funded by the Ministry of Science,ICT&Future Planning(RS-2023–00240010 to M.M.,NRF-2022R1A6A3A13053190 and RS-2024–00450135 to Y.N.,RS-2023–00212388 to S.K.,and RS-2023–00273557 to Y.H.P.)a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea(RS-2023-KH138733 to M.M.).
文摘Alzheimer’s disease(AD)is the most common type of dementia.Monoclonal antibodies(MABs)serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors,such as amyloid-β(Aβ)peptide,tau protein,and neuroinflammation.Specifically,based on their efficacy in removing Aβplaques from the brains of patients with AD,the U.S.Food and Drug Administration has approved three anti-amyloid MABs,aducanumab(AduhelmR),lecanemab(LeqembiR),and donanemab(Kisunla™).Notably,lecanemab received traditional approval after demonstrating clinical benefit,supporting the Aβcascade hypothesis.These MABs targeting Aβare categorized based on their affinity to diverse conformational features of Aβ,including monomer,fibril,protofibril,and plaque forms of Aβas well as pyroglutamate Aβ.First-generation MABs targeting the non-toxic monomeric Aβ,such as solanezumab,bapineuzumab,and crenezumab,failed to demonstrate clinical benefit for AD in clinical trials.In contrast,secondgeneration MABs,including aducanumab,lecanemab,donanemab,and gantenerumab directed against pathogenic Aβspecies and aggregates have shown that reducing Aβdeposition can be an effective strategy to slow cognitive impairment in AD.In this review,we provide a comprehensive overview of the current status,mechanisms,outcomes,and limitations of second-generation MABs for the clinical treatment of AD.Moreover,we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.
